Synthesis of (Dibromocyclobuta) aromatic compounds

ABSTRACT

A method for the synthesis of cyclobuta aromatic compounds by cyclizing two ortho dibromoalkyl substituents is described. Using a mediator, such as nickel metal, and continuous removal of product from contact with the mediator, high product yields are achieved. A method for bromination of ortho alkyl substituents of aromatic compounds is also described.

FIELD OF THE INVENTION

[0001] The present invention is directed to methods for the synthesis of(dibromocyclobuta) aromatic compounds, and more particularly to a highyield method of synthesizing bis (dibromocyclobuta) aromatic compounds.

BACKGROUND OF THE INVENTION

[0002] Polyacenes are polymers predicted to show industrially importantproperties including non-linear optics and high-temperaturesuperconductivity, see references 1. Unfortunately, confirmation of thepredicted properties has not yet been performed due to the lack of anefficient method to prepare polyacenes.

[0003] Cyclobutabenzenes, especially the 7,8-dibromo derivatives 2(depicted in scheme 1), are valuable synthons for functionalizedortho-quiodimethanes that can be trapped by Diels-Alder reactions. Theproduct of such a reaction is a tetrahydronaphtalene 4 derivative havingtwo cis bromine atoms in the 1 and 4 positions. If the dienophile hastwo cis hydrogen atoms, and since the Diels-Alder addition is completelyendo, these hydrogen atoms end the reaction antiperiplanar to thebromine atoms. Such an orientation facilitates elimination of two HBrmolecules to form the corresponding naphtalenic system 6 as described inreference 2 and depicted in scheme 1:

[0004] Reference 4 discloses the Diels-Alder condensation of7,8,9,10-tetrabromo-[1,2][4,5] bicyclobutabenzene 16 withtetracyanoethylene 18, scheme 2:

[0005] Reference 4 further discloses the Diels-Alder condensation of twoequivalents of 7,8-dibromo cyclobutabenzene 2 with one equivalent of1,4-benzoquinone 12 to form the bis-adduct that eliminates fourequivalents of HBr to form the pentacyclic quinone 14, scheme 3:

[0006] Thus, it is expected that of 7,8,9,10-tetrabromo-[1,2][4,5]bicyclobutabenzene 16 can react with benzoquinone 12, in analogy toschemes 2 and 3, to form polyquinone 20, scheme 4:

[0007] As further seen in scheme 4, subsequent reduction of polyquinone20 is expected to yield polyacene 22.

[0008] As the use of non-brominated bicyclobutabenzene would result intwo saturated centers between the aromatic and quinone moieties,deconjugating the polyacene 20, to synthesize polyquinone 20 it isnecessary to use the brominated bicyclobutabenzene, compound 16 or anyof the four all-trans tetrabromo isomers thereof. For the Diels-Aldercondensation to take place, two bromine atoms on a cyclobutane ring mustbe in a trans orientation.

[0009] A number of methods for synthesizing compound 16 or any of thefour all-trans bromo isomers thereof have been disclosed. Reference 5discloses a synthesis of compound 16 using iodide-mediated ring closureand reports a 2% yield. Reference 4 describes a synthesis of compound 16using stochiometric amounts of (Bu₃P)₂Ni(COD) and reports a 10% yield.

[0010] The bottleneck of the above-proposed route of synthesizingpolyacenes such as 22 is the preparation of compounds such as 16. Theknown methods of synthesizing compound such as 16 suffer from lowyields.

[0011] It would be highly advantageous to have a high-yield synthesisfor (trans dibromocyclobuta) aromatic compounds such as 16.

REFERENCES

[0012] 1. a. Kivelson, S.; Chapman, O. L. Phys. Rev. 1993, b28, 7326.

[0013] b. Tanaka, K.; Ohzeki, K.; Yata. S. Synth. Metals 1984, 9, 41.

[0014] c. Ozaki, M. Ikedo, Y.; Nagoya, I. Synth. Metals 1989,28 C801.

[0015] 2. Stanger, A.; Askenazi, N.; Shachter, A.; Blaser, D.;Stellberg, P.; Boese, R. J. Org. Chem. 1996, 61, 2549.

[0016] 3. Stanger, A.; Askenazi, N.; Boese, R.; Blaser, D.; Stellberg,P.; Chem. Eur. J. 1997, 3, 208.

[0017] 4. a. Stanger, A.; Shachter, A.; Askenazi, N.; Boese, R. andStellberg, P. “Nickel Mediated Cyclobutabenzenes Syntheses” in OrganicSynthesis via Organometallics OSM 5, Helmchen, G.; Dibo J.; Flubacher,D.; Wiese, B.: Eds. Friedrich Vieweg & Sohn Verlags GmbH,Braunschweig/Wiesbaden, 1997, pp. 59-66.

[0018] b. Shachter, A. “Cyclobutabenzenes: An Entry to a New SyntheticMethodology” D.Sc Thesis, Technion, Haifa, Israel, 1997.

[0019] 5. Sheferd, M. K. J. Chem. Soc. Perkin Trans I 1988, 961.

SUMMARY OF THE INVENTION

[0020] The present invention is directed to a method for the synthesisof a (dibromocyclobuta) aromatic compound by cyclicizing two orthodibromomethyl substituents of an aromatic moiety. In the product, abromine atom of an individual cyclobutyl ring is predominantly trans tothe other bromine atom of the same cyclobutyl ring.

[0021] The method of the present invention is exceptionally suitable forsynthesizing aromatic compounds substituted with multipledibromocyclobutane rings, especially when the substrate includes a1,2,3,4 or 1,2,4,5 tetra (dibromomethyl) aromatic ring.

[0022] Reference 3 describes a nickel-mediated synthesis for thesynthesis of hexabromo-tricyclobutabenzene 8, scheme 5:

[0023] However, under the conditions of scheme 5,hexabromo-tricyclobutabenzene 8 undergoes butyl ring opening to yieldhexabromo-hexaradialene 10, so that the final yield of the reaction is35% compound 8 and 30% compound 10. In the analogous reaction (notdepicted) using 1,2,4,5-tetra dibromomethyl benzene to produce compound16, only an 8% yield of compound 16 is achieved.

[0024] While not wishing to be held to any one theory, it is likely thatthe low yield of compound 16 using a reaction analogous to that depictedin scheme 5 is a result of decomposition of compound 16 by contact withthe nickel mediator, probably to an undefined polymeric material. Bymodifying the nickel-mediated synthesis described in scheme 5 so as toremove compound 16 formed before decomposition, the method of thepresent invention provides for an efficient method of producing a(dibromocyclobuta) aromatic compound.

[0025] There is provided according to the teachings of the presentinvention a method for the preparation of an aromatic product having atleast one dibromocyclobuta substituent wherein two bromine atoms of anindividual cyclobutane ring are in a trans orientation, by dissolving asubstrate having an aromatic moiety with at least two orthodibromomethyl substituents in a reaction solvent (preferably containingDMF). The dissolved substrate is brought in contact with a mediator(preferably nickel, especially as nickel metal powder). Subsequent tocyclization, contact of a cyclicized product with the mediator islimited to prevent product decomposition.

[0026] The cyclization reaction is preferably performed at an elevatedtemperature.

[0027] According to a feature of the present invention, limiting thecontact of the cyclicized product with the mediator is achieved by usinga continuous flow of solvated substrate through a reaction vessel, suchas a column, containing substantially immobilized mediator.

[0028] According to an additional feature of the present invention,limiting the contact of the cyclicized product with the mediator isachieved by using a two-phase solvent. The first phase is the reactionsolvent and the second phase is an extraction solvent, where thecyclicized product is more soluble in the extraction solvent than thesubstrate is. Preferably the extraction solvent is a mixture of one ormore apolar solvents such as straight chain, branched or cyclic alkylsolvents, petrol ethers, hexane, cyclohexane, heptane,methylcyclohexane, octane, nonane, decane, decalin and the such.

[0029] Preferably, throughout the reaction, product-containingextraction solvent is removed and replenished from the reaction vessel.

[0030] According to the teachings of the present invention there isprovided a method for the preparation of a compounds of the generalformula:

[0031] wherein two bromine atoms of an individual cyclobutane ring arein a trans orientation according to the method described hereinabove,wherein the substrate is

[0032] and where R₁, R₂, R₃, R₄, R₅, and R are independently selectedfrom a group consisting of hydrogen, halogen, straight alkyl, branchedalkyl, cycloalkyl, substituted alkyl, alkyl aryl, aryl, substitutedaryl, heterocycle alkenyl, cycloalkenyl, ether, thioether, amide, amine,alcohol, nitro, thioester, ester, aldehyde and ketone and especiallywhere R₃, R₄, R₅, and R₆ are hydrogen atoms.

[0033] According to the teachings of the present invention there is alsoprovided a method for the preparation of compounds of the generalformula:

[0034] wherein two bromine atoms of an individual cyclobutane ring arein a trans orientation according to the method described hereinabove,wherein the substrate is

[0035] and where R₁, R₂, R₃, R₄, R₅, and R₆ are independently selectedfrom a group consisting of hydrogen, halogen, straight alkyl, branchedalkyl, cycloalkyl, substituted alkyl, alkyl aryl, aryl, substitutedaryl, heterocycle alkenyl, cycloalkenyl, ether, thioether, amide, amine,alcohol, nitro, thioester, ester, aldehyde and ketone and especiallywhere R₃, R₄, R₅, and & are hydrogen atoms.

[0036] In the reactions of the present invention described above, it isclear to one skilled in the art that since predominately the transisomer of the dibromocyclobuta substituent result, then depending on thesymmetry of the substrate a mixture of three or four isomers results.The art of separation of the various isomers from a mixture resultingfrom the present invention is known to one skilled in the art.

[0037] The cyclization reaction of the present invention describedhereinabove requires an ortho bis(dibromomethyl) aromatic substrate.Thus, the method of the present invention further includes a method ofbromination of alkyl groups (especially methyl groups) attached toaromatic moieties (especially benzene derivatives). The method is basedon the irradiation with light of an alkyl-substituted aromatic compoundin the presence of molecular bromine. Unlike the methods known in theart, the present method is based on performing the reaction in achloroform-containing solvent.

[0038] Thus, there is also provided according to the teachings of thepresent invention a method of bromination by dissolving a substratehaving an alkyl substituent on an aromatic moiety in achloroform-containing solvent. The dissolved substrate is heated(preferably to the boiling point under reflux conditions) and irradiatedwith electromagnetic radiation (preferably visible light, and morepreferably light including a wavelength that leads to the production ofbromine radicals).

[0039] The bromination method of the present invention is exceptionallysuited for the dibromination of methyl substituents of aromatic moietiesto yield the dibromomethyl substituent. The bromination method of thepresent invention is even more exceptionally suited for thetetrabromination of ortho dimethyl substituents of aromatic moieties toyield the α, α, α′, α′-tetrabromo-ortho-xylene moiety.

[0040] According to the teachings of the present invention, there isprovided a method as described hereinabove for the preparation of acompound of the general formula:

[0041] wherein R₁ and R₂ are independently selected from a groupconsisting of hydrogen, halogen, straight alkyl, branched alkyl,cycloalkyl, substituted alkyl, alkyl aryl, aryl, substituted aryl,heterocycle alkenyl, cycloalkenyl, ether, thioether, amide, amine,alcohol, nitro, thioester, ester, aldehyde and ketone;

[0042] and wherein R₃, R₄, R₅, and R₆ are independently selected from agroup consisting of hydrogen, fluorine, chlorine, iodine, straightalkyl, branched alkyl, cycloalkyl, substituted alkyl, alkyl aryl, aryl,substituted aryl, heterocycle alkenyl, cycloalkenyl, ether, thioether,amide, amine, alcohol, nitro, thioester, ester, aldehyde and ketone, andespecially where R₃, R₄, R₅, and R₆ are hydrogen atoms.

[0043] Specifically, the present invention provides a method ofbrominating 1,2,4,5-tetramethylbenzene (durene) to yield 1,2,4,5-tetra(dibromomethyl) benzene as well as a method of brominating 1,2,3,4-tetramethylbenzene to yield 1,2,3,4-tetra (dibromomethyl) benzene, a compounduseful for producing [1,2][3,4]tetrabromo bicyclobutabenzene. Clearly,the present invention provides a method for bromination of thederivatives of 1,2,4,5-tetra methylbenzene and 1,2,3,4-tetra(dibromomethyl) benzene to yield the respective brominated derivativesof 1,2,4,5-tetra (dibromomethyl) benzene and [1,2][3,4] tetrabromobicyclobutabenzene.

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The invention is herein described, by way of example only, withreference to the accompanying drawings, wherein:

[0045]FIG. 1 is of a device useful in implementing the first embodimentof the present invention;

[0046]FIG. 2 is of a device also useful in implementing the firstembodiment of the present invention; and

[0047]FIG. 3 is of a device useful in implementing the second embodimentof the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0048] The present invention is of a method for the synthesis of a(dibromocyclobuta) aromatic compound by cyclicizing an aromatic compoundhaving two ortho dibromomethyl substituents. In the product, a bromineatom of an individual cyclobutyl ring is predominantly trans to theother bromine atom of the same cyclobutyl ring.

[0049] The principles of the synthesis of the present invention may bebetter understood with reference to the drawings, the accompanyingdescription and the examples hereinbelow. Two specific embodiments ofthe cyclization of the present invention are discussed in detailhereinbelow: using a two-phase solvent or using a continuous flow ofsubstrate through a column-immobilized mediator. It should not beconstrued that the present invention be limited by the specific chemicalreactions and conditions listed.

[0050] It is important to note that, as described hereinabove, themethod of the present is specifically directed at cyclization of tetra(dibromomethyl) benzenes to yield tricyclic systems. The innovativeconditions of the present invention yield only small amounts of theincompletely cyclicized bis (dibromomethyl) cyclobutyl benzene product.

[0051] The method of the present invention as discussed hereinspecifically relates to the cyclization of tetra (dibromomethyl)benzenes, as this is a class of compounds where double cyclization isexceptionally difficult. It is clear to one skilled in the art, however,that the method of the present invention can be applied to thecyclization of any aromatic compound having two ortho dibromomethylsubstituents. Methods of cyclization known in the art give asubstrate-dependent yield of between 3.8% and 85%. It is expected thatfor any given substrate the method of the present invention will give asignificantly improved yield when compared to the yields of prior artmethods.

[0052] Cyclization of ortho bis(dibromomethyl) aromatic compounds usinga multi-phase solvent system

[0053] According to the first embodiment of the present invention, thesubstrate (an ortho bis (dibromomethyl) aromatic compound) and amediator are placed in a reaction vessel with a reaction solvent. Anextraction solvent is added to the reaction vessel. The reaction mixtureis agitated and heated so as to allow cyclization of the substrate. Oncecyclization occurs and the product is formed, due to solubilityconsiderations the product enters the extraction solvent and is nolonger in contact with the mediator, preventing subsequentdecomposition. Methods of isolation and purification of the product fromthe extraction solvent are well known to one skilled in the art.

[0054] Specifically the first embodiment of the present inventionincludes using nickel, especially in the form of nickel metal powder asa mediator and

[0055] preferably at least about 0.5 equivalents of mediator tosubstrate,

[0056] more preferably at least about 1 equivalents of mediator tosubstrate,

[0057] even more preferably at least about 2 equivalents of mediator tosubstrate,

[0058] and most preferably at least about 5 equivalents of mediator tosubstrate.

[0059] Any starting concentration (M) of starting material in thereaction solvent can be used, but more often between 0.01 and 2,preferably between 0.01 and 1, more preferably between 0.01 and 0.5,  even more preferably between 0.02 and 0.2,   and most preferably between0.07 and 0.1.

[0060] Generally, the substrate of the present invention is soluble inpolar solvents such as DMF (dimethylformamide) but only slightly solublein non-polar solvents. Although not wishing to be held to any onetheory, it is believed that the DMF acts as a ligand to stabilizereactive organometallic intermediates (such as a mediator-substratecomplex).

[0061] It is important to note that using the method of the presentinvention, the brominated substrate needs not be soluble in the reactionsolvent. Although not wishing to be held to any one theory, it isbelieved that in cases when the substrate is only barely or not solublein the reaction solvent, the DMF acts to solubilize the reactiveorganometallic intermediates (such as a mediator-substrate complex). Incases where the substrate is not soluble in the reaction solvent, theamount of substrate above is calculated as actual and not asconcentrations, as is clear to one skilled in the art.

[0062] Thus, it is desirable that the reaction solvent is any solvent ormixture of solvents containing DMF. Preferably the reaction solvent isso composed that at the beginning of the reaction there are at least 2equivalents DMF for every equivalent substrate; more preferably thereare at least 10 equivalents DMF for every equivalent substrate; evenmore preferably there are at least 25 equivalents DMF for everyequivalent substrate and most preferably there are at least 50equivalents DMF for every equivalent substrate. If other factors allow,substantially neat DMF can be used as a reaction solvent of the presentinvention. It is important to note that, generally speaking, the rate ofreaction is faster with an increasing DMF component in the reactionsolvent.

[0063] It is obvious to one skilled in the art that it is ideal that thesubstrate be barely or not at all soluble in the extraction solvent. Itis equally obvious to one skilled in the art that it is alsoadvantageous that the product be slightly or not all soluble in thereaction solvent.

[0064] As is clear to one skilled in the art, the greater the solubilityof the product in the extraction solvent and the lesser the solubilityof the product in the reaction solvent the greater the ultimate yieldshall be. Thus ideally: 1) the product is at least slightly soluble, andpreferably soluble in the extraction solvent 2) the substrate issubstantially insoluble in the extraction solvent 3) the reactionsolvent and extraction solvent are substantially immiscible or at leastproduce a two-phase solvent system.

[0065] Despite this, the choice of solvents is not unlimited and eachset of substrate and product have different solubility characteristics.Therefore, the minimal requirement of the first embodiment of thepresent invention to get a reasonable yield is that the extractionsolvent is any solvent or mixture of solvents that upon mixing with thereaction solvent yields a solvent system having at least two-phases, anextraction phase and reaction phase, so that the product is at leastsomewhat soluble in the extraction phase. In such a “minimal” case it ispossible to remove product-containing extraction phase from the reactionvessel and to replenish it with fresh extraction solvent. When freshextraction solvent is added to the reaction, even if the product is lesssoluble in the extraction phase than in the reaction phase, there is apartition of the product between the two solvent phases. Even if asignificant proportion of the product remains in the reaction phase, bycontinuously removing product-containing extraction phase and addingfresh extraction solvent, product is continuously removed from thereaction even if the product is only slightly soluble in the extractionphase.

[0066] Considering the nature of the expected products, a mixture of oneor more apolar solvents such as straight chain, branched or cyclic alkylsolvents, petrol ethers, hexane, cyclohexane, heptane,methylcyclohexane, octane, nonane, decane, decalin and the such arepreferred-components of an extraction solvent of the present invention.

[0067] The reaction temperature can be between 40° and 150° C.,preferably between 50° and 120° C., more preferably between 60° and 100°C., even more preferably between 70° and 90° C., and most preferablybetween 75° and 85° C. As is clear to one skilled in the art, it ispreferable that the reaction temperature be lower than the boilingpoints of both the extraction and the reaction solvents. In the casewhere it is chosen to use a temperature that is somewhat higher than theboiling point of one of the two solvents, a reflux apparatus can be usedto allow condensation and recovery of the evaporated solvents. Due tothe fact that when the reaction solvent boils mixing is too vigorous, itis preferable that the reaction temperature be always lower than theboiling point of the reaction solvent.

[0068] As is clear to one skilled in the art, the reaction of thepresent invention can also be performed in a closed system at elevatedpressures.

[0069] It is necessary to ensure that the mediator-is in effectivecontact with the reaction solvent and that there be sufficient contactbetween the reaction solvent and the extraction solvent to allowefficient transfer of cyclicized product from the reaction solvent tothe extraction solvent. On the other hand, it is necessary to minimizecontact of product-containing extraction solvent with the mediator.Thus, the intensity of agitation, whether thermal or mechanical, needsto be regulated with the aforementioned factors in mind.

[0070] As noted above, for the reaction yield be maximal, it ispreferred that product-containing extraction phase be removed from thereaction vessel during the reaction, preferably continuously removed.When the product-containing extraction phase is removed from thereaction vessel during the reaction, it is preferable to concurrentlyreplenish the extraction phase by adding a substantially equal amount offresh extraction solvent.

[0071] It is preferable that the extraction solvent be less dense thenthe reaction solvent, so that product containing extraction solvent canbe easily collected from the top of the reaction vessel withoutinterference from mediator which tends to collect at the bottom of thereaction vessel.

[0072] In FIG. 1, a reaction vessel 10 useful for implementing the firstembodiment of the method of the present invention is depicted. Reactionsolvent 12 (DMF) is denser than extraction solvent 14 (heptane). Due toits density, a mediator powder 16 remains in reaction solvent 12.Mechanical stirrer 18 causes sufficient agitation to prevent settling ofmediator powder 16 at the bottom of vessel 10, ensuring contact betweenmediator powder 16 and substrate dissolved in reaction solvent 12.Additional extraction solvent is continuously added through feed tube20. The addition of extraction solvent through feed tube 20 causes acontinuous overflow of product-containing extraction solvent throughport 22. Overflow is collected for subsequent product isolation. Heatingis provided by oil bath 24.

[0073] It is also possible to implement the first embodiment of thepresent invention when the extraction solvent is denser then thereaction solvent, the excess extraction solvent is collected from thebottom of the reaction vessel. In such a case care is taken to preventinsoluble material such as the mediator from being removed from thereaction along with the product.

[0074] In FIG. 2, a reaction vessel 26 useful for implementing the firstembodiment of the method of the present invention is depicted. Reactionsolvent 12 is less dense than extraction solvent 14. Due to the presenceof a porous sintered glass layer 28 mediator powder 16 remains inreaction solvent 12 although reaction solvent can freely flow throughglass layer 28 to make contact with extraction solvent 14. Mechanicalstirrer 18 causes sufficient agitation to prevent settling of mediatorpowder 16 on glass layer 28, ensuring contact between mediator powder 16and substrate dissolved in reaction solvent 12. Product containingextraction solvent 14 is continuously drained through port 22.Additional extraction solvent is continuously added through feed tube 20to maintain a sufficient amount of solvent in vessel 26.

[0075] Cyclization of ortho bis(dibromomethyl)aromatic Compounds UsingContinuous-Flow Through Column-Immobilized Mediator

[0076] According to the second embodiment of the present invention, thesubstrate (an ortho bis(dibromomethyl) aromatic compound), dissolved ina reaction solvent, is streamed through a column (or functionallyequivalent device) containing an immobilized mediator, preferablynickel, especially as nickel metal powder. As the substrate flowsthrough the column, contact of substrate with the mediator leads toformation of the desired product. Preferably the column is heated toallow efficient cyclization of the substrate. Clearly, theinterdependence of the reaction conditions, such as the exact nature ofthe reaction solvent, the flow rate of flow, the condition of themediator the nature of the substrate, the length of the column and thetemperature necessitates optimization of every specific reaction. As isclear to one skilled in the art, optimization involves identifying a setof conditions that lead to maximal product formation yet minimal productcontact with the mediator.

[0077] Specifically the second embodiment of the present inventionincludes using any starting concentration (M) of starting material inthe reaction solvent, but more often between 0.01 and 2, preferablybetween 0.01 and 1, more preferably between 0.01 and 0.5,   even morepreferably between 0.02 and 0.2,   and most preferably between 0.05 and0.08.

[0078] The reaction solvent chosen is as specified hereinabove for thefirst embodiment of the present invention.

[0079] The rate of flow of reaction solvent through the reaction columncan be anything, but more often (in units of seconds to pass onecolumn-volume of solvent) between 1 and 560, preferably between 5 and240, more preferably between 10 and 120, even more preferably between 15and  45, and most preferably between 18 and 22.

[0080] The reaction temperature can be between 40° and 160° C.,preferably between 80° and 160° C., more preferably between 100° and140° C., even more preferably between 110° and 130° C., and mostpreferably between 115° and 125° C.

[0081] Methods of isolation and purification of the product from theproduct-containing reaction solvent collected from the terminal end ofthe column is clear to one skilled in the art.

[0082] A column 30, suitable for realizing the second embodiment of thepresent invention is depicted in FIG. 3. Substrate containing reactionsolvent is introduced through inlet 32 of column 30. As the reactionsolvent flows through column 30, substrate reacts to yield productaccording to the method of the present invention by interaction withimmobilized mediator powder 34. In FIG. 3, mediator powder 34 isimmobilized in glass wool. Product-containing solvent drips out throughstopcock 36 and is collected. Column 30 is jacketed, allowing heating ofsolvent inside column 30 by the introduction of a heated liquid throughport 38.

[0083] Bromination of Alkyl Groups Attached to Aromatic Compounds

[0084] Most generally, bromination according to the method of thepresent invention is a light-catalyzed bromination of alkyl groupsattached to an aromatic substrate dissolved in chloroform at reflux byaddition of molecular bromine.

[0085] An aromatic compound with at least one alkyl group is dissolvedin chloroform and placed in a reaction vessel configured so as to allowreflux of the solution. The solution is allowed to reflux and irradiatedwith light; Br₂ is added in portions to the refluxing chloroformsolution. After the reaction is complete, reflux and irradiation arestopped and the brominated product isolated from the chloroform.

[0086] Preferably, sunlight or a sunlight lamp is used to irradiate thereaction mixture. More preferably, light containing a wavelengthsufficient to produce bromine radicals is used.

[0087] The starting concentration (M) of starting material in thechloroform solvent can be anything, but more often between 0.01 and 2,preferably between 0.01 and 1, more preferably between 0.01 and 0.5,  even more preferably between 0.02 and 0.2,   and most preferably between0.07 and 0.1.

[0088] Isolation and purification of the product can be performed usingany of the methods known to one skilled in the art.

[0089] It is important to note that in the art, for example, a 76% yieldof 1,2,4,5-tetra (dibromomethyl) benzene can be achieved by reactingdurene under similar conditions using CCl₄ as a reaction solvent.Unexpectedly and unpredictably, a 96% yield is achieved using the methodof the present invention that is using chloroform as a solvent.

SPECIFIC SYNTHETIC EXAMPLES

[0090] Bromination of Durene to Yield Octabromodurene

[0091] Br₂ (46.6 ml, 0.907 mole) was added dropwise to a refluxingsolution of durene (2.964 gr., 0.022 mol) in chloroform (220 ml). Theheat and light needed for the reaction were supplied by a 375 W sunlightlamp. The end of the reaction (after about 5 days) was determined by ¹HNMR. The reaction mixture was cooled to room temperature and neutralizedwith a 5% aqueous NaHCO₃ solution. The solid product was filtered,washed with a 10% thiosulphate solution, water and methanol. After themethanol wash the product was dried in high vacuum until constant weightachieved. Obtained were 16.095 gr. (96% yield) of octabromodurene.

[0092] Cyclization of Octabromodurene

Example A Two-Phase Solvent

[0093] Metallic nickel powder (1.157 gr., 0.0197 mol), octabromodurene(1.507 gr., 1.969 mmol) and DMF (26 ml) were placed in a 50 mol reactionvessel. Heptane was added to fill the vessel. The reaction mixture washeated to 80° C. and additional heptane was introduced using a syringepump at a rate of 10 ml/hour. The heptane overflow was collected. DMFwas added from time to time to compensate for its loss as under thesemi-improvised conditions used some DMF “escaped” to the heptane phase.After 9 days the collected heptane phase was evaporated using vacuum. Anamount of chloroform sufficient to dissolve the product-containingresidue was added and adsorbed, onto 1 gram Florisil® (60-100 meshactivated magnesium silicate, CAS nr. 1343-88-0) and chloroform removedunder vacuum. The product adsorbed on the Florisil® was placed on top ofan open topped Florisil®-packed chromatographic column and eluted usingchloroform. The chloroform solution was washed with 5% HCl, 5% NaHCO₃,water, and dried over MgSO₄. A 22% yield of [1,2][4,5] tetrabromobicyclobutabenzene 16 was obtained.)

Example B Immobilized Nickel

[0094] Metallic nickel powder (6.5 gr.) spread on glass wool was placedin a jacketed column (10 mm internal diameter) so that the height of thenickel on glass wool was 5 cm. The column was heated to 120° C., and asolution of octabromodurene (1.54 gr., 2 mmol) in warm DMF (32 ml) wasallowed to pass through the column at a rate of 1 drop/sec. After allthe octabromodurene solution was added, neat EMT was introduced into thecolumn at a rate of 1 drop/sec until the solution dripping from thecolumn was colorless. The total amount DMF added was approximately 70ml. The DMF was evaporated and the product isolated as described inExample A. A 28% yield of tetrabromo bicyclobutabenzene 16 was obtained.

[0095] Bromination of 1.2,3,4-tetramethyl Benzene to Yield 1.2.3.4-tetra(Dibromomethyl) Benzene

[0096] Br₂ (46.6 ml, 0.907 mol) is added dropwise to a refluxed solutionof 1,2,3,4-tetramethylbenzene (2.964 gr., 0.022 mol) in chloroform (220ml). The heat and light needed for the reaction are supplied by a 375 Wsunlight lamp. The end of the reaction is determined by ¹H NMR. Thereaction mixture is cooled to room temperature, and then neutralizedusing a 5% aqueous HaHCO₃ solution. The solid product is filtered,washed with 10% thiosulphate solution, water and methanol, and dried inhigh vacuum until constant weight achieved. Obtained is 1,2,3,4-tetrakisdibromomethyl benzene.

[0097] Cyclization of Octabromo 1,2,3,4-tetramethylbenzene

Example C Two-Phase Solvent

[0098] Metallic nickel powder (1.157 gr., 0.0197 mol),tetrakis(dibromomethyl) benzene (1.507 gr., 1.969 mmol) and DMF (26 ml)are placed in a 50 ml reaction vessel and heptane is added to fill thevessel. The reaction mixture is heated to 80° C. and heptane isintroduced by a syringe pump at a 2-10 ml/hour rate. The overflow iscollected.

[0099] Some DMF is added from time to time to compensate for loss of DMFto the heptane phase. The collected heptane is evaporated in vacuum.Chloroform and Florisil® are added to the residue, and dried in vacuum.The product adsorbed on the Florisil® is placed on top of an open toppedFlorisil®-packed chromatographic column, and the product eluted withchloroform. The chloroform solution is washed with 5% HCl, 5% NaHCO₃,water, and dried over MgSO₄. Obtained is tetrabromo [1,2][3,43]bicyclobutabenzene.

Example D Immobilized Nickel

[0100] Metallic nickel powder (6.5 gr.) spread on glass wool is placedin a jacketed column (10 mm internal diameter) so that the height of thenickel on glass wool is 5 cm. The column is heated to 120° C., and asolution of tetrakis(dibromomethyl)benzene (1.54 gr., 2 mmol) in warmDMF (32 ml) is allowed to pass through the column in the rate of 1drop/sec. The column is washed with DMF until the solution dripping fromthe column is colorless. The DMF is evaporated and the product worked upas described in Example C. Obtained is tetrabromo-[1,2][3,4]bicyclobutabenzene.

What is claimed is:
 1. A method for the preparation of product, theproduct being an aromatic compound with at least one dibromocyclobutasubstituent, comprising: a. providing a substrate having an aromaticmoiety including at least two ortho dibromomethyl substituents; b.dissolving said substrate in a reaction solvent; c. providing amediator; d. bringing said dissolved substrate in contact with saidmediator to mediate a cyclization reaction; and e. limiting subsequentcontact of the product, produced by said cyclization reaction, with saidmediator.
 2. The method of claim 1 wherein said mediator comprisesnickel.
 3. The method of claim 2 wherein said mediator comprises nickelmetal powder.
 4. The method of claim 1 wherein said aromatic moiety ofsaid substrate includes at least four dibromomethyl substituents, eachone of said at least four dibromomethyl substituents being ortho to atleast one other of said at least four dibromomethyl substituents.
 5. Themethod of claim 1 wherein said reaction solvent comprises DMF (dimethylformamide).
 6. The method of claim 5 wherein said reaction solventcomprises at least about 2 equivalents DMF for every 1 equivalentsubstrate.
 7. The method of claim 6 wherein said reaction solventcomprises at least about 10 equivalents DMF for every 1 equivalentsubstrate.
 8. The method of claim 7 wherein said reaction solventcomprises at least about 25 equivalents DMF for every 1 equivalentsubstrate.
 9. The method of claim 8 wherein said reaction solventcomprises at least about 50 equivalents DMF for every 1 equivalentsubstrate.
 10. The method of claim 5 wherein said reaction solvent issubstantially neat DMF.
 11. The method of claim 1 wherein said limitingof subsequent contact comprises substantially immobilizing said mediatorin a reaction vessel and bringing said dissolved substrate in temporarycontact with said immobilized mediator by letting said dissolvedsubstrate flow through said reaction vessel.
 12. The method of claim 11wherein a temperature of said reaction solvent in said reaction vesselis elevated.
 13. The method of claim 12 wherein said temperature isbetween 40° C. and 160° C.
 14. The method of claim 13 wherein saidtemperature is between 80° C. and 160° C.
 15. The method of claim 14wherein said temperature is between 100° C. and 140° C.
 16. The methodof claim 15 wherein said temperature is between 110° C and 130° C. 17.The method of claim 16 wherein said temperature is between 115° C. and125° C.
 18. The method of claim 11 wherein a starting concentration ofsaid substrate in said reaction solvent is between 0.01 M and 2 M. 19.The method of claim 18 wherein a starting concentration of saidsubstrate in said reaction solvent is between 0.01 M and 1 M.
 20. Themethod of claim 19 wherein a starting concentration of said substrate insaid reaction solvent is between n 0.01 M and 0.5 M.
 21. The method ofclaim 20 wherein a starting concentration of said substrate in saidreaction solvent is between 0.02 M and 0.2 M.
 22. The method of claim 21wherein a starting concentration of said substrate in said reactionsolvent is between 0.05 M and 0.08 M.
 23. The method of claim 1 whereinsaid limiting of subsequent contact comprises providing an extractionsolvent selected so that upon mixing of said extraction solvent and saidreaction solvent, a solvent system having at least two-phases, a firstreaction phase and a second extraction phase, is formed so that theproduct is at least slightly soluble in said second extraction phase.24. The method of claim 23 wherein said limiting of subsequent contactfurther comprises removing a portion of said second extraction phasecontaining the product from said solvent system.
 25. The method of claim24 wherein said limiting of subsequent contact further comprises addingfresh extraction solvent to said solvent system so as to compensate forsaid removing of said portion of said product-containing secondextraction phase.
 26. The method of claim 25 wherein said removing iscontinuous.
 27. The method of claim 23 wherein said extraction solventis less dense than said reaction solvent.
 28. The method of claim 23wherein said extraction solvent comprises a mixture of individualsolvents.
 29. The method of claim 23 wherein said extraction solventcomprises at least one apolar solvent.
 30. The method of claim 29wherein said extraction solvent comprises at least one of the apolarsolvents from the group consisting of straight chain alkanes, branchedalkanes, cyclic alkanes, petrol ethers, hexane, cyclohexane, heptane,methylcyclohexane, octane, nonane, decane and decalin.
 31. The method ofclaim 23 wherein said extraction solvent is further selected so as to besubstantially immiscible with said reaction solvent and wherein saidsubstrate is substantially insoluble in said extraction solvent.
 32. Themethod of claim 23 wherein a temperature of said first reaction phase iselevated.
 33. The method of claim 32 wherein said temperature is between40° C. and 150C.
 34. The method of claim 33 wherein said temperature isbetween 50° C. and 120° C.
 35. The method of claim 34 wherein saidtemperature is between 60° C. and 1001C.
 36. The method of claim 35wherein said temperature is between 70° C. and 90° C.
 37. The method ofclaim 36 wherein said temperature is between 75° C. and 85° C.
 38. Themethod of claim 32 wherein said temperature of said first reaction phaseis substantially a boiling temperature of said second extraction phase.39. The method of claim 32 wherein said temperature of said firstreaction phase is substantially a boiling temperature of said firstreaction phase.
 40. The method of claim 23 wherein at a start of saidreaction there is at least about 10.5 equivalents mediator relative tosaid substrate.
 41. The method of claim 40 wherein at a start of saidreaction there is at least about 1 equivalents mediator relative to saidsubstrate.
 42. The method of claim 41 wherein at a start of saidreaction there is at least about 2 equivalents mediator relative to saidsubstrate.
 43. The method of claim 42 wherein at a start of saidreaction there is at least about 5 equivalents mediator relative to saidsubstrate.
 44. The method of claim 23 wherein a starting concentrationof said substrate in said first reaction phase is between 0.01 M and 2M.
 45. The method of claim 44 wherein a starting concentration of saidsubstrate in said first reaction phase is between 0.01 M and 1 M. 46.The method of claim 45 wherein a starting concentration of saidsubstrate in said first reaction phase is between 0.01 M and 0.5 M. 47.The method of claim 46 wherein a starting concentration of saidsubstrate in said first reaction phase is between 0.02 M and 0.2 M. 48.The method of claim 47 wherein a starting concentration of saidsubstrate in said first reaction phase is between 0.07 M and 0.1 M. 49.A method for the preparation of a compound of the formula

wherein two bromine atoms of an individual cyclobutane ring are in atrans orientation, according to the method of claim 1 wherein saidsubstrate is

where R₁, R₂, R₃, R₄, R₅, and R₆ are independently selected from a groupconsisting of hydrogen, halogen, straight alkyl, branched alkyl,cycloalkyl, substituted alkyl, alkyl aryl, aryl, substituted aryl,heterocycle alkenyl, cycloalkenyl, ether, thioether, amide, amine,alcohol, nitro, thioester, ester, aldehyde and ketone.
 50. A compound ofclaim 49 where R₃, R₄, R₅, and R₆ are hydrogen atoms.
 51. A method forthe preparation of a compound of the formula:

wherein two bromine atoms of an individual cyclobutane ring are in atrans orientation, according to the method of claim 1 wherein saidsubstrate is

and where R₁, R₂, R₃, R₄, R₅, and R₆ are independently selected from agroup consisting of hydrogen, halogen, straight alkyl, branched alkyl,cycloalkyl, substituted alkyl, alkyl aryl, aryl, substituted aryl,heterocycle alkenyl, cycloalkenyl, ether, thioether, amide, amine,alcohol, nitro, thioester, ester, aldehyde and ketone.
 52. A method ofclaim 51 where R₃, R₄, R₅, and R₆ are hydrogen atoms.
 53. A method forbromination comprising a providing a substrate having an aromatic moietywith at least one alkyl substituent; b. dissolving said substrate in asolvent; c. placing said substrate dissolved in said solvent in areaction vessel; d. heating said reaction vessel; and e. irradiatingsaid substrate dissolved in said solvent with electromagnetic radiation.wherein said solvent comprises chloroform.
 54. The method of claim 53wherein said substrate has an aromatic moiety with at least two orthoalkyl substituents.
 55. The method of claim 53 wherein saidelectromagnetic radiation includes components having visible lightwavelengths.
 56. The method of claim 53 wherein said solvent comprisesat least 90% by weight of chloroform.
 57. The method of claim 56 whereinsaid solvent comprises at least 97% by weight of chloroform.
 58. Themethod of claim 57 wherein said solvent comprises substantially neatchloroform.
 59. The method of claim 53 wherein said heating is to aboiling point of said solvent.
 60. The method of claim 53 wherein astarting concentration of said substrate in said reaction solvent isbetween 0.01 M and 2 M.
 61. The method of claim 60 wherein a startingconcentration of said substrate in said reaction solvent is between 0.01M and 1 M.
 62. The method of claim 61 wherein a starting concentrationof said substrate in said reaction solvent is between 0.01 M and 0.5 M.63. The method of claim 62 wherein a starting concentration of saidsubstrate in said reaction solvent is between 0.02 M and 0.2 M.
 64. Themethod of claim 63 wherein a starting concentration of said substrate insaid reaction solvent is between 0.07 M and 0.1 M.
 65. The method ofclaim 53 wherein at least one of said at least one alkyl substituent isa methyl substituent.
 66. A method for the preparation of a compound ofthe general formula:

according to the method of claim 53 wherein R₁ and R₂ are independentlyselected from a group consisting of hydrogen, halogen, straight alkyl,branched alkyl, cycloalkyl, substituted alkyl, alkyl aryl, aryl,substituted aryl, heterocycle alkenyl, cycloalkenyl, ether, thioether,amide, amine, alcohol, nitro, thioester, ester, aldehyde and ketone; andwherein R₃, R₄, R₅, and R₅ are independently selected from a groupconsisting of hydrogen, fluorine, chlorine, iodine, straight alkyl,branched alkyl, cycloalkyl, substituted alkyl, alkyl aryl,, aryl,substituted aryl, heterocycle alkenyl, cycloalkenyl, ether, thioether,amide, amine, alcohol, nitro, thioester, ester, aldehyde and ketone. 67.The method of claim 66 where R₃, R₄, R₅, and R₆ are hydrogen atoms. 68.A method for the preparation of a compound of the general formula:

according to the method of claim 53 wherein R₁ and R₂ are independentlyselected from a group consisting of hydrogen, halogen, straight alkyl,branched alkyl, cycloalkyl, substituted alkyl, alkyl aryl, aryl,substituted aryl, heterocycle alkenyl, cycloalkenyl, ether, thioether,amide, amine, alcohol, nitro, thioester, ester, aldehyde and ketone; andwherein R₃, R₄, R₅, and R₆ are independently selected from a groupconsisting of hydrogen, fluorine, chlorine, iodine, straight alkyl,branched alkyl, cycloalkyl, substituted alkyl, alkyl aryl, aryl,substituted aryl, heterocycle alkenyl, cycloalkenyl, ether, thioether,amide, amine, alcohol, nitro, thioester, ester, aldehyde and ketone. 69.The method of claim 68 where R₃, R₄, R₅, and R₆ are hydrogen atoms.